title: Investigation into the mechanism(s) of antithrombotic effects of carbon monoxide releasing molecule-3 (CORM-3).
abstract: Carbon monoxide (CO) like nitric oxide (NO) has been recognized as activator of soluble guanylate cyclase (sGC) in many physiological functions. Studies, which demonstrate the mechanisms by which CO inhibits platelet aggregation in in vivo models, are few. Here we investigated the possible involvement of sGC, NO, plasminogen activator inhibitor (PAI-1) and p38 MAP Kinase in antithrombotic effects of CO released by a novel, water-soluble, CO releasing molecule-3 (CORM-3) using rat. The effects of CORM-3 on in vitro and ex vivo platelet aggregation induced by thrombin as well as in in vivo thrombosis models were studied. When added to rat washed platelets in in vitro study, CORM-3 (100 and 200 μM) inhibited thrombin-induced platelet aggregation. Similarly, antiplatelet effect was also observed when 3mg/kg i.v. infusion of CORM-3 administered for 10 minutes in ex vivo study using rat. Interestingly, in presence of inhibitor of sGC (ODQ, 10mg/kg,i.p.) and inhibitor of nitric oxide synthase (L-NAME, 30 mg/kg,i.p.), inhibition of thrombin-induced aggregation by CORM-3 was significantly blocked. Notably, in presence of inhibitor of K(ATP) channel (glibenclamide, 10mg/kg,i.p.) and p38 MAP Kinase (SCIO-469, 1mg/kg, i.p.), inhibition of aggregation by CORM-3 was not blocked. In in vivo studies using animal models of thrombosis, we found that CORM-3-mediated antithrombotic effect was dependent on activation of sGC, NO and suppression of PAI-1 in arterial thrombosis and Arterio-Venous (A-V) shunt models. Therefore, we concluded that antithrombotic activity of CORM-3 may be mediated by activation of sGC, NO and inhibition of PAI-1.
authors.affiliation: Zydus Research Centre, ZRC communication No # 331), Sarkhej-Bavla NH 8A Moraiya, Ahmedabad 382210, India.
authors.forename: Hitesh
authors.initials: H
authors.lastname: Soni
authors.forename: Mukul
authors.initials: M
authors.lastname: Jain
authors.forename: Anita A
authors.initials: AA
authors.lastname: Mehta
mesh_terms: D000818:Animals; D000991:Antithrombins / Q000493:pharmacokinetics / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects; D002248:Carbon Monoxide / Q000493:pharmacokinetics / Q000494:pharmacology*; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D009942:Organometallic Compounds / Q000493:pharmacokinetics / Q000494:pharmacology*; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D013917:Thrombin / Q000494:pharmacology; D013927:Thrombosis / Q000097:blood / Q000188:drug therapy; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000991:Antithrombins; D009942:Organometallic Compounds; D017395:Plasminogen Activator Inhibitor 1; C476530:tricarbonylchloro(glycinato)ruthenium(II); D002248:Carbon Monoxide; D048051:p38 Mitogen-Activated Protein Kinases; D013917:Thrombin